Intrinsic modulation of neutrophil antifungal activity against Candida albicans

Neutropenia is an independent risk factor for the development of invasive aspergillosis and carries an increased risk for disseminated infection and impaired outcome in Candida bloodstream infection. Results of project C3 from the first funding period have confirmed the central role of polymorphonuclear leukocytes (PMN) in the defense against invasive fungal infections. Importantly, these findings also corroborate the hypothesis that PMN activation is largely determined by intrinsic mediators like C5a, which is required for both early PMN activation during infection and activation of bystander PMN that are not in direct physical contact with the invading pathogen. We provide evidence that PMN activation is specific to the pathogen and differs not only between fungi of different genera (Candida albicans and Aspergillus fumigatus) but also between more closely related species (C. albicans and Candida glabrata). Building on these results we will continue to analyze networks of PMN activation focussing on: (i) Communication of PMN within human blood. The interaction of PMN with other components of human blood, including monocytes and NK cells will be further dissected. To identify important signaling pathways, we will extend comparative analyses with C. glabrata while continuing comparative analyses with A. fumigatus. A new focus will be directed at the role of human platelets in providing secondary stimuli for PMN activation. (ii) Pathogen specific activation of PMN. Work in the first funding period revealed that PMN induce distinct patterns of activation in response to different fungal pathogens. Making use of C. albicans and C. glabrata as model organisms we aim to dissect the molecular basis for this differential recognition and response. This “intra-genus” comparison will be complemented by a continuation of comparative analyses with A. fumigatus. (iii) PMN activation and fungal immune escape. We will continue to elucidate the novel immune escape mechanism that enables the persistence of viable extracellular C. albicans cells in human blood for prolonged time periods. Initial work suggested a central role of PMN in the removal of host proteins that mediate fungal recognition including C3b and iC3b and we now aim to dissect the molecular mechanisms underlying this cellular remodeling.